The present proposal is a renewal application for USPHS grant ES-0-1005 which was awarded during 1974-1979. This application extends the work on toxicology in ES-0-1055 by examining in detail using various tissue culture systems, animal models, and man the interacting effects of environmental chemicals, drugs, hormones, nutrition and genes on the biology and function of the heme-cytochrome P-450 systems. We will extend our earlier work on developing micro-assays for enzymes and components of the heme pathway since heme, serving as the prosthetic group of cytochrome P-450, plays a key role in the detoxification (and sometimes activation) of endogenous and exogenous chemicals. Tissue model systems are used extensively to study the biological impacts of environmental chemicals and newly developed techniques which include isolated nervous system cultures, alveolar macrophage cultures, erythroid differentiation (Friend-virus infected cells) and mitogen-stimulated lymphocytes show considerable promise in helping to elucidate the actions of organic pollutants and toxic metals, on cellular differentiation and metabolism. Study of the toxicity of organometals for heme-P-450 systems are newly planned and already reveal major deleterious effects of these substances on heme mediated functions. Biological protective mechanisms against certain toxic metals are examined and studies of the role of nutritional factors in modifying (enhancing/increasing) the biological impacts of chemicals in man are proposed. Humans receive the bulk of their exposure to exogenous chemicals through their diet - and since the proteins, carbohydrates and fats themselves contain chemicals which affect the heme-P-450 systems nutritional/toxicological interactions of clinical importance can be anticipated. Finally, extensive studies of the metabolism of steroid hormones and of the heme-P-450 systems in various worker populations exposed to specific environmental chemicals at work sites are planned in order to determine the nature and extent of derangements of these systems which our preliminary studies (lead, PCB workers) have already shown may characterize such high-risk populations.